Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial—Protocol and statistical analysis plan

Introduction

Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods

The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion

The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

     

Skin protection against methylmethacrylate

Ordinary surgical rubber gloves are penetrated by methylmethacrylate monomer (MMA) in less than 1 minute, as demonstrated by gas chromatographic measurements. A three-layered PVP glove, 0.07 mm thick - consisting of an outer layer of polyethylene, an intermediary layer of ethylene vinyl alcohol copolymer, and an inner layer of polyethylene - was impervious for 20 minutes, whereas a viton-butyl rubber glove, 0.27 mm thick, was impervious for 15 minutes.

The PVP glove is recommended to orthopedic surgeons, nurses, and other handling acrylic bone cements to avoid sensitization, and is especially recommended to persons with known contact allergy to MMA.     

Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.     

Die „kleine“ Handverletzung im BGlichen Heilverfahren

Only a small percentage of “minor” hand injuries are treated by surgeons with a specialist training in hand surgery, partly because they are so frequent. In most cases this does not prejudice the outcome. There are, however, still patients whose treatment takes an unexpectedly long time and who are not successfully rehabilited but are left with lasting problems justifying early retirement. To face up to these problems, which are often the result of inadequate or inappropriate treatment, a model hand surgery project established as part of the treatment plan by several of the regional branches of the German employers’ liability insurance associations (Southwest Germany, Berlin, Brandenburg, Mecklenburg-Upper Pomerania, and Northwest Germany) has been in place since spring 2002. This project and the experience recorded in patients treated according to the procedures laid down for it are presented in this paper.     

Iotrol versus metrizamide in lumbar myelography: a double-blind study

In a prospective, randomized, double-blind study, 49 patients underwent lumbar myelography using iotrol (24 patients) or metrizamide (25 patients). The diagnostic imaging adequacy of iotrol was comparable with that of metrizamide. After iotrol myelography, adverse reactions were fewer, less severe, and of shorter duration than were those following metrizamide myelography. Thirteen of 24 patients (54%) receiving iotrol reported some adverse reactions compared with 24 of 25 patients (96%) receiving metrizamide. Five moderate and one severe adverse reaction occurred in the group receiving iotrol. Fourteen moderate and eight severe adverse reactions occurred in the group receiving metrizamide. Thirty-eight patients underwent electroencephalography both before and after myelography (19 iotrol and 19 metrizamide). None of the EEGs obtained after iotrol myelography changed from baseline, while seven of the EEGs obtained after metrizamide myelography showed changes from baseline. Iotrol was judged superior to metrizamide as a contrast medium in this patient population.     

31P NMR spectroscopic study of bioenergetic changes in radiation-induced fibrosarcoma-1 after radiation therapy

The effects of localized gamma-irradiation on the in vivo 31P NMR spectra of RIF-1 tumors grown subcutaneously in C3H/HeN mice have been examined before and during the week after treatment. Increases in the ratio of phosphocreatine (PCr) to inorganic phosphate (Pi) and in tumor pH, and decreases in the ratio of Pi to the beta phosphorus resonance of the nucleotide triphosphates (beta NTP) were observed in irradiated tumors. The time course of changes in the 31P spectrum following treatment was the opposite of the pattern during untreated growth, and the magnitude and duration of the changes increased with increasing radiation dose, decreasing clonogenic cell survival and increasing growth delay. To examine the possibility that nontherapeutic systemic effects of the tumor irradiation were responsible for the changes observed, a number of animals bearing two tumors were examined. One tumor on each mouse was selectively irradiated. Changes in tumor volume, Pi/beta NTP, PCr/Pi, the ratio of phosphomonoesters to beta NTP, and tumor pH were all significantly different in the treated compared to the untreated tumor on each animal, indicating that these changes in 31P NMR spectra were a response to radiation therapy and not a systemic response to radiation toxicity.     

Season of birth and risk of atopic disease among children and adolescents.

BACKGROUND: Season of birth (SOB) has been regarded as a risk factor for atopy. The aim of this study was to explore the relationship between season of birth (SOB) and later development of atopic disease in children and adolescents. METHODS: A total of 1,007 randomly selected subjects, 7 to 17 years of age, who were living in urban Copenhagen, Denmark were studied. All participants were interviewed about respiratory symptoms and possible risk factors for atopic disease. Skin test reactivity, serum total immunoglobulin E (IgE), and airway responsiveness were measured using standard techniques. RESULTS: The overall risk of atopy, as judged by skin test reactivity and serum total IgE, was the same regardless of SOB. On the contrary, asthma was more common in subjects born in the autumn compared with subjects born during the remaining part of the year (12.4% vs. 5.6%), OR = 2.40, 95% CI (1.56-3.94), p < 0.001. This was observed both for atopic asthma OR = 2.41, 95% CI (1.25-4.64), p = 0.007, non-atopic asthma, OR = 2.35, 95% CI (1.14-4.83), p = 0.02, and house dust mite (HDM) sensitive airway hyperresponsiveness, OR = 3.00, 95% CI (1.44-6.24), p = 0.002. Rhinitis and pollen allergy were not significantly related to SOB. CONCLUSIONS: Atopy itself is independent of season of birth, whereas asthma is more prevalent among subjects born during the autumn. Regarding asthma, these results suggest that the first months of life enclose a period of particular vulnerability towards environmental risk factors, especially exposure to aeroallergens like HDM.     

Precise and accurate measurement of proton T1 in human brain in vivo: Validation and preliminary clinical application

Precise and accurate inversion-recovery (PAIR) magnetic resonance (MR) measurements of T1 were obtained in eight brain regions and cerebrospinal fluid of 26 healthy volunteers. Accuracy of the technique was assessed by measuring T1 in small fluid volumes with the PAIR technique and with two independent spectroscopic techniques. The mean difference between T1 measured with PAIR and with the two spectroscopic techniques was 3.1% ± 1.3. The precision (reproducibility) of measurements with the PAIR technique was excellent. The coefficient of variation (CV) across 16 measurements in a head phantom was 2.0%, compared with a CV of 2.7% across 45 separate measurements in a single subject. The within-subject CV was 1.8% ± 0.6 in white matter and 1.4% ± 1.0 in basal ganglia. The between-subject CV in 26 healthy volunteers was 3.6% ± 0.6 in white matter and 4.1% ± 1.9 in basal ganglia. Comparison between a patient with an active recurrent brain tumor and an agematched patient with an inactive brain tumor showed that T1 was significantly elevated throughout the brain of the active-tumor patient, especially in white matter tracts, even though no tumor or edema was detected in the white matter on standard MR images. Comparisons between five brain tumor patients and four healthy volunteers of similar age showed that T1 was significantly and substantially elevated throughout the white matter tracts and in the caudate nucleus, putamen, and thalamus. These results are consistent with the hypothesis that white matter tracts are selectively vulnerable to edema and that T1 increases in white matter are a sensitive indicator of patient status or tumor aggressiveness.     

Myocardial sestamibi single-photon emission tomography: Variations in reference values with gender, age and rest versus stress?

Reference data files support the evaluation of myocardial perfusion single-photon emission tomography (SPET). The aim of this study was to create a large reference data base for technetium-99m sestamibi SPET, age and gender matched to the general patient population. One hundred and twenty-eight healthy volunteers (76 males and 52 females) with a likelihood of coronary artery disease of less than 5% underwent rest and maximal exercise^99mTc-sestamibi SPET with a 2-day protocol and 180° elliptical rotation. The normalized activity values of^99mTc-sestamibi in the inferior wall differed significantly between men and women. Age variations were found for men in the anterior wall. Normalized activity values in all four walls were strikingly similar during rest and stress. Our results suggest that the use of reference files in^99mTc-sestamibi SPET requires a gender- and, for males, possibly an age-matched reference population. Different reference files at rest and during stress might not be necessary.